Multi-model Oscillation Based Connectivity Theory Applied to the Integration of Bio-Sensory Data

1. Global Clock Synchronisation 

In computing many emerging sensor network applications require that the sensors in the network agree on the time. A global clock in a sensor system will help process and analyze the data correctly and predict future system behavior. For example, in the vehicle tracking application, each sensor may know the time when a vehicle is approaching. By matching the sensor location and sensing time, the sensor system may predict the vehicle moving direction and speed. Without a global agreement on time, the data from different sensors cannot be matched up. Other applications that need global clock synchronization include environment monitoring (for example, temperature), navigation guidance, and any other application that requires the coordination of locally sensed data and mobility.  Q Li 2004.

In these systems various approaches have been taken to temperature compensation  e.g Q Li 2004. S Chauhan 2012.   J M Castillo-Secilla 2013. 

A similar approach could potentially be taken to synchronising biosensors. A Prindle 2015T Danino 2009. J Hasty 2008,  J V Selinger 2003,

This posting considers whether a similar mechanism to global clock sychronisation could be connecting together biological sensors (using  the Transient Receptor Potential (TRP) superfamily of ion channels), and supporting temperature compensation.

Another posting on this site explores how this could also support the operational of neural networks.

2. The Biological Clock

Evidence suggests that circadian clocks control a number of biological processes through an organism in both plants and animals. A N Dodd – ‎2015C. Robertson McClung 2010.  To this day, circadian clocks remain one of the most robust experimental systems wherein perturbations of genetic background or environmental state can be directly linked to changes in physiology and behaviour. Lisa Wulund 2015.

Even though daily temperature fluctuations serve as a synchronizing signal for circadian clocks, clocks are also temperature compensated. This means that when kept under constant conditions (i.e., no daily fluctuations of either light/dark or temperature), circadian clocks tick at the same speed at low or high constant temperatures.  It is crucial that circadian clocks are temperature compensated, because a clock that runs with different speed at different temperatures would not be a clock (rather a thermometer).  Stanewsky’s Lab (UCL). 

There is also a strong relationship between metabolic (redox-based circadian oscillators) and circadian pathways e.g. M U Gillette 2014C B Peek 2012, J S O’Neill 2014 in Circadian Redox and Metabolic Oscillations in Mammalian Systems.   Similar to clock dependent circadian rhythms, these oscillations are temperature-entrainable and temperature-compensated. C B Peek 2012.   This posting now focuses on circadian (including redox) rhythms. However it should be noted that circadian rhythms are linked to and supported by a range of other biological rhythms (of varying periods A Goldbeter 2007).

3. Global Clock Synchronisation of Biosensors

R Campan in “the Orientation and Communication of Arthropods” (edited by M Lehrer 1997) argues that taxes (e.g geotaxis, chemotaxis, magnetotaxis) provide the foundations for understanding orientation –  as their main function is to assist in the ecological adaptation of the animal to the constraints of its environment.

The sandhopper uses a number of orientation mechanisms including phototaxis, geotaxis, scototaxis, polarotaxis, astrotaxis, and magnetotaxis (Pardi & Scapini 1987). They also possess the capacity to use local cues such as landmarks, wave activity, substrate channels, slopes, humidity and sand grain (Scapini et al 1992).  The use of different orientation strategies (in a single species) must be synchronised, and biological clocks and pulses could provide such synchronisation.

A time synchronised sensory system could support neural activity (e.g supporting foraging) and infection resistance.

Interestingly the “foraging gene” found in various species is thought to linked to phototaxis, chemotaxis, learning and memory, and circadian rhythms. KK Ingram – ‎2011.

4. The Transient Receptor Potentials

Key to understanding how global clock sychronisation could be connecting together biological sensors  is the relationship between biological rhythms and the Transient Receptor Potential (TRP) superfamily of ion channels.

TRPs are activated through a wide variety of mechanisms and participate in virtually every sensory modality. These are essential for navigating through an ever changing environment. From insects to mammals TRP channels are known mediators for cellular sensing.  Mammalian TRP channel proteins are polymodal cation channels that participate in sensory physiology at different levels. These include thermosensation, mechanosensation, nociception (sensation of noxious stimuli), touch, taste, olfaction, and vision. Under physiological conditions, TRP channel opening allows for the fast entrance of sodium and calcium ions into the cell. Although originally found in Drosophila melanogaster (relevant findings on Drosophila are summarised towards the end of this posting) , at present, TRP channels are mostly studied in mammalian cells.  LuisArias-Darraz 2015.

In humans, the TRP superfamily of cation channels includes 27 related molecules that respond to a remarkable variety of chemical and physical stimuli. While physiological roles for many TRP channels remain unknown, over the past years several have been shown to function as molecular sensors in organisms ranging from yeast to humans.  H Wang 2015. 

TRPs are very sensitive to temperature, and are widely found in vertebrate and invertebrate neurons, and when activated result in an influx cations into cells.  Temperature sensitivity or TRPs in the mammalian cortex and hippocampus are not well understood. However there is some evidence that they response to temperature in ways that may influence synaptic plasticity. MG Frank – ‎2016

TRPs and biological clocks

TRPs are also becoming seen as a missing bond in the entrainment mechanism of peripheral clocks throughout evolution.  Recently, in vertebrates and more specifically in the rainbow trout Oncorhynchus mykiss, the involvement of TRPV1 with rhythms of melatonin secretion has been demonstrated. The pharmacological blockade of pinealocyte TRPV1 inhibited melatonin secretion. Although the data linking thermo-TRP and biological rhythms are still scarce, and most of them were demonstrated in central clocks, valuable information has been provided to trace parallels between the role of thermo-TRP in central and peripheral synchronization.   M O Poletini 2015. 

Links have been made to the expression of circadian-clock genes and TRPV1. S C Yang 2015.

The relationship between circadian rhythms and redox may also be implicated. TRPs act as signal integrators of redox status changes.  N Takahasi 2011.  A group of cation-permeable channels that are formed by transient receptor potential (TRP) proteins have been characterized as exquisite sensors of redox reactive species and as efficient actuators of electric/ionic signals in vivo. Y Mori 2016 Reactive species activate TRP channels either directly through oxidative amino acid modifications or indirectly through second messengers.  N Ogawa 2016. Y Mori 2016.

TRPs and Magnetosensitivity

It is asked whether these channels could be involved in magnetoreception (utilising radical pairs)?

In mice, Ferritin nanoparticles associate with a camelid anti-GFP–transient receptor potential vanilloid 1 fusion protein, αGFP-TRPV1, and can transduce noninvasive RF or magnetic fields into channel activation, also showing that TRPV1 can transduce a mechanical stimulus. This, in turn, initiates calcium-dependent transgene expression.   S A Stanley 2015. 

Researchers have demonstrated calcium ion influx in neurons after injecting 22 nm sized magnetic nanoparticles into brain tissue and exciting the neurons by activating heat-sensitive capsaicin receptors (transient receptor potential cation channel subfamily V member 1 : TRPV1) using an external AC magnetic field i.e. nano-magneto thermal excitation.  R Chen 2015.

A single-component, magnetically sensitive actuator, “Magneto,” has been created comprising the cation channel TRPV4 fused to the paramagnetic protein ferritin.  Scientists validated noninvasive magnetic control over neuronal activity by demonstrating remote stimulation of cells using in vitro calcium imaging assays, electrophysiological recordings in brain slices, in vivo electrophysiological recordings in the brains of freely moving mice, and behavioral outputs in zebrafish and mice. Results present Magneto as an actuator capable of remotely controlling circuits associated with complex animal behaviors. M A Wheeler 2016.

Another researcher had already stated that  they had found that magnetic activation of TRPV4 channels enables remote control of cell function in the absence of chemical or biological agents (although this article has been withdrawn). O Lunov 2013. 

In addition to osmosensing neurons, TRPV4 has been found in other CNS structures, including the choroid plexus, substantria negra, hippocampal CA1, thermo-regulatory neurons, astrocytes, and retinal cells.  The physiological role of TRV4 in these regions is unknown.  TRPV4 MRNA levels have been found to be dependent on circadian rhythms (Suzuki 2012). It has also been found that clock genes regulate circadian rhythms of Piezo1 and TRPV4 expressions and intracellular Ca2+ influx after stretch stimulation in cultured urothelial cells. T Ihara 2016.  

It would be interesting to see what effect CG8198/MagR would have on TRPV4 and TRPV1.



A. Chlamydomonas reinhardtii (a unicellular organism)

Chlamydomonas reinhardtii shows circadian rhythms in many biological processes, such as phototaxis, chemotaxis, cell division, cell adhesion, starch content, sensitivity to UV irradiation, and nitrogen metabolism. The circadian regulation of these processes confers adaptive advantages including positive phototaxis during the day which allows cells to accumulate in light-rich environments and achieve efficient photosynthesis.  Similarly chemotaxis during the night enables them to find nitrogen-rich environments before their nitrogen uptake and metabolism peaks in the morning.  The circadian rhythms in these processes suggest that the underlying gene expression is regulated by a circadian clock.  Indeed, many studies have described circadian rhythms at the mRNA level e.g, a genome wide DNA microarray analysis revealed that the expression of -2.6% of the nuclear genes in C.Reinhardtii is regulated by the circadian clock.   It should be noted that there is considerable similarity between the circadian clocks of C.reinhardtii and A thaliana. T Matsuo – ‎2011.

Although TRP channels seem to be absent in plants, C. reinhardtii possesses genomic sequences encoding  TRP proteins.  The cloning and characterization of a C. reinhardtii version of a TRP channel shared key features present in mammalian TRP channels associated with sensory transduction….Several other single-celled organisms appear to possess sequences encoding TRP channels, including Dictyostelium (The Slime Mould), Trypanosoma, Leishmania, and Plasmodium.  LuisArias-Darraz 2015

B) Caenorhabiditis Elegans 

Thermotaxis is especially important in small ectotherms such as C. elegans and Drosophila, whose small mass  means they have small heat capacities.  The sensitivity of fly and nematode body temperature to environmental temperature changes is paralleled by the striking sensitivity of their thermosensory systems. A commonality between the C. elegans and Drosophila is that they both use thermotactic navigation. It has been an intriguing and largely unanswered question how a small circuit, using thermosensory information from the C. elegans AFD neurons, is endowed with the flexibility to drive the distinct sensorimotor transformations that underlie different modes of thermotactic movement in different temperature ranges.   P Garrity 2010. In vertebrates, thermosensation is predominantly governed by TRP channels.

JM Gray at al – ‎2005 provides further findings on the links between neurons, chemotaxis and thermotaxis.  After Caenorhabiditis elegans are removed from bacterial food, they initiated a local search behavior consisting of reversals and deep omega-shaped turns triggered by olfactory neurons, gustatory neurons, and interneurons. Over the following 30 min, the animals disperse as reversals and omega turns are suppressed by gustatory neurons and interneurons. Interneurons and motor neurons downstream encode specific aspects of reversal and turn frequency, amplitude, and directionality. Motor neurons help encode the steep amplitude of omega turns, specify the ventral bias of turns that follow a reversal, and  set the amplitude of sinusoidal movement. Many of these sensory neurons, interneurons, and motor neurons are also implicated in chemotaxis and thermotaxis. Thus, this circuit may represent a common substrate for multiple navigation behaviors.

By examining magnetotaxis in mutant Caenorhabiditis elegans worms that lack responses to particular sensory stimuli, Vidal-Gadea et al. found that a pair of neurons called the AFD neurons – which were already known to carry information about temperature and chemical stimuli from the environment (Mori and Ohshima 1995 – are critical for magnetic navigation. C H Rankin 2015.   There is multi-sensory integration of chemosensory and thermosensory information in chemotaxis behavior of the C. elegans. R Adachi 2008.

In transgenic C Elegans, expressing  MagR/Cry protein complex in myo-3-specific muscle cells or mec-4-specific neurons, application of an external magnetic field triggered muscle contraction and withdrawal behaviour of the worms, indicative of magnet-dependent activation of muscle cells and touch receptor neurons.  X Long 2016.

Research has only recently begun to reveal information about the molecular and neural components of the C.elegans circadian clock.  It is known that it displays biological cycles, such as the molt cycle and  circadian locomotor rhythms.  However, notable is the absence in C. elegans of proteins similar to the Cryptochromes (CRY) of both insects and mammals, however a novel photoreceptor family has been discovered in C. elegans.  This nematode exhibit a negative phototactic behavior towards UV and blue light. A Romanowski 2014.  

C) Drosophila

Drosophilia uses thermotaxis  L Lu 2010, S Lahiri 2011, and chemotaxis A Gomez-Marin 2011A Schulze 2015  as navigation strategies.

Drosophila larval thermotaxis behaviors appear to be driven by thermosensory neurons activated by either high or low temperatures and that are connected to a shared downstream circuitry to mediate negative or positive thermotaxis behaviors, respectively. Larval chordotonal neurons have also been reported to respond to temperature variations, and, in the adult, chordotonal neurons have been implicated in temperature entrainment of the circadian clock.   Thermal information processing in Drosophila relies on histamine as a neurotransmitter, but the specific neuronal populations involved have not been identified.  S-T Hong 2006.

Recent work in Drosophila has demonstrated that sensory receptors normally associated with other modalities, such as chemical sensing, can also make important contributions to thermotransduction. In particular, GR28B(D), a member of the invertebrate gustatory receptor (GR) family, was shown to function as a warmth receptor to mediate warmth avoidance in adult flies exposed to a steep thermal gradient (Ni et al., 2013). The photoreceptor Rhodopsin has also been reported to contribute to temperature responses, although its role in thermosensory neurons is unexamined (Shen et al., 2011).

Drosophila is also magnetoreceptive R J Gegear 2010. The Drosophilas circadian clock is sensitive to the magnetic fields and this depends on the activation of cryptochrome and on the applied field strength. The flies exposed to the static magnetic fields enhanced slowing of clock rhythms and this effect was maximal at 300 μT C D. Abeyrathne 2010.

An electromagnetic field disrupts negative geotaxis in Drosophila via a Cry dependent pathway. CRYs may sense EMFs via formation of radical pairs of electrons requiring photoactivation of flavin adenine dinucleotide (FAD) bound near a triad of Trp residues, but mutation of the terminal Trp in the triad maintains EMF responsiveness in climbing. In contrast, deletion of the CRY C terminus disrupts EMF responses, indicating that it plays an important signalling role. CRY expression in a subset of clock neurons, or the photoreceptors, or the antennae, is sufficient to mediate negative geotaxis and EMF sensitivity.G Fedele – ‎2014

Several genes have been shown to alter geotaxis in Drosophila. Two of these genes, cryptochrome (cry) and Pigment-dispersing-factor (Pdf) are integral to the function of biological clocks. Pdf plays a crucial role in maintaining free-running circadian periods. The cry gene alters blue-light (<420 nm) phototransduction which affects biological clocks, spatial orientation and taxis relative to gravity, magnetic fields, solar, lunar, and celestial radiation in several species. The cry gene is involved in phase resetting (entrainment) of the circadian clock by blue light (<420 nm).

Geotaxis involves spatial orientation, so it might be expected that geotaxis is linked genetically with other forms of spatial orientation. The association between geotaxis and biological clocks is less intuitive.  However geotaxis and circadian behaviours in drosophila are tied together in an interesting pleiotropic relationship, but several investigators have failed to find circadian variation in geotaxis maze scores of wild-type D. melanogaster or in strains selected for geotaxis.  It has been suggested that this has been due to the contrast of the Lo and Hi5 geo-flies with wild-type flies – with artificial selection playing havoc with gene pools adapted to natural conditions.

Wild-type D. melanogaster also orient in magnetic fields, but mutant (cryb), flies do not. The circadian clock of wild-type D. melanogaster is slowed (longer tau) in constant magnetic fields, in a dose dependent manner, but only in blue light and with a functional cry gene. Interestingly, cry-dependent magnetosensitivity does not require a functioning circadian clock, but it does require a functional cry gene.   cry’s functional requirement for blue light (<420nm) in phase shifting circadian clocks and in altering spatial orientation and taxis in several species relative to gravity, magnetic fields, solar, lunar, and celestial radiation  makes it the most interesting of the genes currently associated with both biological clocks and geotaxis.

Research shows genes, physiology and behavioural aspects of geotaxis, circadian clocks, magnetosensitivity and spatial orientation are complex, intriguing and interrelated. D L Clayton 2016.

Drosophila, TRPs and Circadian Rhythms. 

Since the cloning and characterization of the gene encoding the Drosophila TRP channel, which functions in phototransduction, twelve other fly TRP channels have been identified. These channels are critical for sensing the external environment, and function in vision, thermosensation, olfaction, taste, hygrosensation, mechanosensation, circadian rhythms. Consequently, these channels have a profound impact on animal behavior. M A Fowler 2014.

Melanopsin and rhodopsin, photopigments present respectively in circadian and visual photoreceptors, are required for temperature discrimination in Drosophila melanogaster. These pigments may signal light and temperature via activation of TRP.  TRPs have been suggested to function as thermal sensor for various groups of animals.  M O Poletini 2015. 

A prominent summer locomotor component (component A) in Drosophilia has been found to be temperature- and clock-dependent and is generated by expression of the internal transient receptor potential A1 thermosensor (TrpA1), revealing a pathway for environmental input to the clock. E W Green 2015. 

The Drosophila TRPA1 channel is a candidate for sensing thermal cycles that affect activity rhythms, since it participates in thermotaxis, and is directly activated in a range (>24°C)  that functions in temperature synchronization of circadian rhythms…  It has been proposed that separate sets of central neurons are the most critical for light and temperature entrainment, and cry-negative neurons may be the more important temperature sensors. It is worth noting that some trpA1-positive central neurons are cry negative.  Y Lee 2013.

In the adult form TRPA1 is expressed in a subgroup of pacemaker neurons of the brain. The loss of TRPA1 impaired the temperature-induced syncronization and altered the expression of the clock gene Per in some pacemaker neurons. In peripheral tissues of Drosophila Pyx TRP channel (pyrexia transient receptor potential) located in sensory organs is responsible for the entrainment to lower cycles of temperature (16–20C). The pyrexia transient receptor potential channel mediates circadian clock synchronization to low temperature cycles in Drosophila.  W Wolfgang 2013.

Perhaps, as in the case Caenorhabiditis elegans, Drosophila is using polymodal senses (evolved from taxes) to obtain information about the local environment, and this may be reflected by common neural circuits (TRPs) which link to circadian clocks.  There are multiple regions of the CNS that engage in temperature sensation and thermal information processing. It will be interesting to learn how these pathways interact to regulate thermotaxis, avoidance of noxious heat, and temperature-compensated circadian clocks in Drosophila P Garrity 2010.

There are implications for an integrated system from the emerging link between circadian rhythms and redox.  Perturbation of the transcription–translation feedback loop clockwork or the redox system results in a perturbation of the other, indicating that they have a reciprocal relationship. Lisa Wulund 2015,  A Stangherlin – ‎2013.  The Cryptochrome protein (CRY) in Arabidopsis, Drosophila, and mouse provide the most direct path by which redox status can interact with the core components of the transcription–translation feedback loop  (TTFL).  Lisa Wulund 2015.

D. Other

Other species of immediate interest are the cells of Magnetospirillum gryphiswaldense which unexpectedly display swimming polarity that depends on aerotactic signal transduction through one of its four chemotaxis operons (cheOp1). GF Popp 2014, and the philophthalmus gralli miracidia, where magnetotaxis and geotaxis are coupled to help the larvae to reach the habitat where potential hosts can be found.  The magnetotactic response is similar to that described for magnetobacteria and algae (R Witschko 1995).  In the honeybees waggle dance astrotaxis (or polarotaxis) is combined with geotaxis and magnetotaxis. TRP (Transient Receptor Potential) are found in various species of bees. Ben M Sadd 2015.  Circadian rhythms in odor-evoked physiological responses have also been described in Drosophilia, humans, mice, cockroaches, and moths.  Thermotaxis and Chemotaxis are also utilised in sperm transport.  H A Guidobaldi 2012.

This article merely joins up other peoples work into an overall system.  These works have been referenced so it is clear that others have provided the individual pieces of evidence that have been used to shape a specific systems approach.    



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